Cosmetic or dermatological composition comprising an association between a compound of the N-acylaminoamide family and at least one matrix metalloproteinase inhibitor

ABSTRACT

A cosmetic or dermatological composition characterized in that it comprises an association between an elastase inhibitor compound of the N-acylaminoamide family and at least one metalloproteinase inhibiting compound.

This application claims foreign priority of France application 0108433,filed Jun. 26, 2001.

The present invention relates to the field of cosmetic or dermatologicalcompositions. It relates to novel cosmetic or dermatologicalcompositions comprising an association between an elastase inhibitorcompound of the N-acylaminoamide family and at least one antagonist ofthe synthesis and/or of the release and/or the activity of matrixmetalloproteinases. Such a composition is preferably adapted forimproving the skin ageing and/or photoageing signs, which cutaneoussigns are, as far as some of them are concerned, directly a result of achronic micro-inflammatory process induced by repeated UV exposures.

The human skin consists in two compartments, i.e. a superficialcompartment, the epidermis, and a deep compartment, the derma. Thenatural human epidermis mainly comprises three cell types, which are thekeratinocytes, much in the majority, the melanocytes and the Langerhanscells. Each of such cell types contributes, by virtue of its ownfunctions, to the essential part played in the skin organism.

The derma provides a solid support to the epidermis. It is also itsnutritive element. It consists mainly in fibroblasts and oneextracellular matrix, comprising, in its turn, mainly collagen, elastinand one substance, the so-called fundamental substance, formed withcomponents synthetized by the fibroblast. It also comprises leukocytes,mastocytes or even tissue macrophages. It is also crossed by bloodvessels and nervous fibres.

It is known that during a superficial skin stress, which can normally befrom chemical, physical or bacterial origin, the keratinocytes from theepidermis superficial layers release biological mediators which areadapted to attract some of the skin infiltrating cells, which arethemselves responsible for maintaining a transitory local irritation.

Biological mediators able to be produced by the thus-stressedkeratinocytes include chemokines which are chemoattractive cytokinesresponsible for recruiting leukocytes on inflammatory sites, includingthe interleukin 8 (IL-8) which is more particularly responsible forrecruiting neutrophils.

Such cells infiltrating into the irritated or attacked areas thenrelease enzymes, amongst which me leukocyte elastase can be found. Underthe action of such enzyme among others, the extracellular backingelastic fibres in connective tissue may be altered and thereby lead to areduction of skin elasticity.

Further, it is also known that in synergy with cathepsin G, theleukocyte elastase may dissociate the epidermis integrity by enlargingthe interkeratinocyte intercellular spaces.

Thus, in the long term, the sum of the superficial skin micro-stressesgenerated, for example, by a prolonged UV exposure or by irritatingagents, can lead to a more or less accelerated loss of skin naturalelasticity. The array formed by the elastic fibres in the underlyingconnective tissue and the extracellular spaces can then be progressivelydismantled. This results in an accelerated ageing of the skin (wrinkledand/or less supple skin) with the derma elastic array being altered, aswell as more accentuated wrinkles (deeper wrinkles).

Moreover, it is known that the derma resistance is also ensured bycollagen fibres. Such fibres are made of fibrils sealed to each other,thereby forming more than ten types of various structures. The dermaresistance is also due to an entanglement of collagen fibres which arepacked one onto the other in all directions. The collagen fibrescontribute to the skin and/or mucous membrane elasticity and tonicity.

The collagen fibres are continuously renewed, but such a renewaldecreases over the age which also leads to the derma becoming thinner.This derma thinning is also due to pathological causes such as, forexample, corticoid hormone hypersecretion, some pathologies or evenvitamin deficiencies (which is the case of vitamin C in scorbutus). Itis also recognized that extrinsic factors such as ultraviolet rays,tobacco or some treatments (Glucocorticoids, vitamin D and derivativesfor example) also have an effect on the skin and the matrix protein ratethereof, more particularly collagen.

Though very resistant, the collagen fibres are sensitive to someenzymes, the so-called collagenases. An alteration of the collagenfibres leads to the skin having a soft and wrinkled appearance, againstwhich the human being, preferring the appearance of a smooth and tenseskin, has always tried to fight.

Moreover, in menopause period, the main variations relating to the dermaare an alteration of the elastic tissue and a decrease of the collagenrate and the derma thickness. This leads, in the menopausal woman, tothe skin and/or the mucous membranes becoming thinner. The woman thenhas the feeling of a “dry skin” or of a drawn skin and an increase offine wrinkles and small surface wrinkles can also be noticed. The skinexhibits a rough aspect when touched. Finally, the skin exhibits areduced suppleness.

Upon a (chemical, physical, bacterial or neurogeneous) skin stress, thekeratinocytes release biological mediators (called chemoattractivefactors) which are able to attract some inflammatory cells of the bloodcompartment towards the skin tissue. Such cells are responsible forgenerating, and subsequently, for maintaining a local irritation.

Amongst the chemoattractive factors able to be produced by the stressedkeratinocytes, the interleukin 8 (IL-8) is more specifically responsiblefor recruiting the neutrophil polynuclears. Such cells infiltrating intothe irritated or attacked areas then release enzymes, including theleukocyte elastase and other proteases (metalloproteinases, proteaseserines, etc).

Under the action of such enzyme, the extracellular backing elasticfibres in the connective tissue are altered. In synergy with thecathepsin G, the leukocyte elastase can also dissociate the epidermisintegrity enlarging the interkeratinocyte intercellular spaces(Ludolph-Hauser et al. Exp. Dermatol. 1999 8(1) 46-52). The leukocyteelastase has recently been incriminated in maintaining eschars and inproducing leg venous ulcers, through its fibronectin altering activity(Herrick S et al. Lab. Invest 1997(3) 281-288). The sum of the localizedalteration micro-stresses (resulting, for example, from a prolongedexposure to the sun) can result in the long term in an accelerated lossof the natural elasticity in skin. The underlying connective tissueelastic fibre and the extracellular space array is then progressivelydismantled. This accelerated alteration can be cumulated with the skinnormal ageing process which is characterized by a higher sensitivity ofthe elastic fibres to the elastase action (Stadler R & Orfanos C E Arch.Dermatol. Res. 1978 262 (1) 97-111).

It is known in the state of the art that molecules can be brought in theskin tissue so as to slow down the alteration activity of the elasticfibres in the intercellular spaces.

But this not always satisfactory. Indeed, the fibril array is complexand numerous other enzyme activities can also degrade the elastin andthe collagen and, as a consequence, dismantle and disorganize, through asite distinctive from the elastin, the collageno-elastic cutaneous arraymeshes. Such enzymes can include metalloproteinases and gelatinasesadapted to degrade either the native collagen (like MMP-1, MMP-2 andMMP-14) or the denatured collagen in the form of gelatin (like MMP-9 andMMP-2).

The technical solution according to the invention is to bring, inaddition to the regulating element of the elastase activity (theN-acylaminoamide derivative inhibiting the leukocyte elastase), one ormore active ingredients being able to regulate as well the other enzymeactivities interfering in the skin matrix array integrity, in the formof compositions.

Such a novel association can be used in care cosmetic compositions forareas exposed to the sun (scalp, body, face, lips), in care cosmeticcompositions of ulcerated areas, in tooth-pastes or mouthwash lotionsand, generally, in all the so-called “skin anti-ageing” cosmeticpreparations, the objective of which is to slow down thechronobiological dismantling of backing tissues and the architecture ofthe skin matrix elements.

Consequently, the object of the invention is to provide a cosmetic ordermatological composition characterized in that it comprises anassociation between an elastase inhibiting compound of theN-acylaminoamide family and at least one metalloproteinase inhibitor.

It is understood by “metalloproteinase inhibitor” according to theinvention meaning, an antagonist compound for the synthesis and/or therelease and/or the activity of the matrix metalloproteinases.

Another object of the invention is to provide a cosmetic treating methodfor body or face skin, including the scalp, wherein a cosmeticcomposition such as defined hereunder is applied onto the skin.

In fact, it has been found that the compounds of the formula (I) showedan inhibiting activity of the elastase activity and that they canconsequently be used for limiting and/or fighting against the elasticfibre alteration.

Therefore, they can be used in or for preparing a composition, thecompounds or the composition being adapted to treat, in a preventiveand/or curative way, the ageing skin signs.

The novel association of the N-acylaminoamides with at least onemetalloproteinase inhibitor makes it possible to significantly reinforcethe anti-ageing effect of the matrix tissue by addition of an effectboth on the enzymes involved in the elastin degradation and on theenzymes involved in the collagen degradation.

According to the invention, the regulating element of the elastaseactivity (i.e. the N-Acylaminoamide derivative inhibitor of the enzymeactivity of the leukocyte elastase), the{2-[acetyl-(3-trifluorometyl-phenyl)-amino]-3-methyl-butyrylamino}aceticacid is combined with one or more actives able to inhibit the activity,the synthesis or the release of the skin metalloproteinases.

The resulting composition is adapted to treat ageing disorders and/or tobe more specifically designed to treat all the signs of skin ageingand/or photoageing.

More preferably, this novel association is used in care cosmeticpreparations of the areas exposed to the sun (scalp, body, face, lips),and, generally, in all the so-called “skin anti-ageing” cosmeticpreparations with the objective of slowing down the dismantling of thebacking tissues and the architecture of the skin matrix elements.

Without being bound by any theory, the Applicant thinks that bringing,at the level of the skin superficial layer keratinocytes, compounds ableto slow dawn the altering activity of the intercellular space elasticfibres, makes it possible to reduce this skin accelerated ageingphenomenon, resulting from superficial skin stresses and that theassociation of such compounds with a metalloproteinase inhibitorconsiderably reinforces their effects.

Preferred N-acylaminoamide Compounds

The compounds likely to be used in the present invention have thereforethe following formula (I):

where:

-   -   the Y radical represents O or S,    -   the R¹ radical represents:        -   (i) a hydrogen atom,        -   (ii) a linear, branched or cyclic, saturated or unsaturated            hydrocarbon radical having 1 to 18 carbon atoms,

-   optionally substituted by 1 to 5 groups, either identical or    different, selected amongst —OH; —OR; —O—COR; —SH; —SR; —S—COR;    —NH₂; —NHR; —NRR′; —NH—COR; Hal (halogen); —CN; —COOR; —COR;    —P(O)—(OR)₂; —SO₂—OR; with R and R′ representing, independently from    each other, a linear, branched or cyclic, saturated or unsaturated    hydrocarbon radical having 1 to 6 carbon atoms, optionally being    halogenated or even perhalogenated;

-   said R and R′ radicals being able to form together with N a carbon    ring with 5 to 6 ring members optionally comprising further at least    one heteroatom being selected amongst O, N and/or S in the ring    and/or optionally substituted by 1 to 5 groups, identical or    different, selected amongst —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″;    —NH₂; —NHR″; —NH—COR″; -Hal (halogen); —CN; —COOR″; —COR″; with R″    representing a linear, branched or cyclic, saturated or unsaturated    hydrocarbon radical, having 1 to 6 carbon atoms, optionally being    halogenated, even perhalogenated;    -   -   (iii) a radical selected amongst —OR; —NH₂; —NHR; —NRR′;            —NH—COR; —COOR; —COR;

-   with R and R′ representing, independently from each other, a linear,    branched or cyclic, saturated or unsaturated hydrocarbon radical    having 1 to 6 carbon atoms, optionally being halogenated, even    perhalogenated;

-   said R and R′ radicals being able to form together with N a carbon    ring with 5 to 6 ring members optionally comprising, additionally,    at least one heteroatom selected amongst O, N and/or S in the ring    and/or optionally substituted by 1 to 5 groups, identical or    different, selected amongst —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″;    —NH₂; —NHR″; —NH—COR″; -Hal (halogen); —CN; —COOR″; —COR″; with R″    representing a linear, branched or cyclic, saturated or unsaturated    hydrocarbon radical having 1 to 6 carbon atoms, optionally being    halogenated, even perhalogenated;    -   the R² radical represents a linear, branched or cyclic,        saturated or unsaturated hydrocarbon radical, with 1 to 18        carbon atoms, optionally substituted by 1 to 5 groups, either        identical or different, selected amongst —OH; —OR; —O—COR; —SH;        —SR; —S—COR; —NH₂; —NHR; —NRR′; —NH—COR; Hal (halogen); —CN;        —COOR; —COR; with R and R′ representing, independently from each        other, a hydrocarbon, straight, branched or cyclic, saturated or        unsaturated radical, with 1 to 6 carbon atoms, optionally        halogenated, or even perhalogenated; said R and R′ radicals able        to form together with N a carbon cycle with 5 to 6 chains        optionally comprising, additionally, at least one heteroatom        selected amongst O, N and/or S in the ring and/or optionally        substituted by 1 to 5 groups, identical or different, selected        amongst —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″;        —NH—COR″; -Hal (halogen); —CN; —COOR″; —COR″; with R″        representing a linear, branched or cyclic, saturated or        unsaturated hydrocarbon radical, with 1 to 6 carbon atoms,        optionally halogenated, even perhalogenated;    -   the R³ radical represents a radical selected amongst those of        the formulae (II) or (III):        -A-C₆H_((5-y))—B_(y)  (II)        —C₆H_((5-y′))—B_(y′)  (III)        where:    -   y is an integer between 0 and 5 inclusive, and y′ is an integer        between 1 and 5 inclusive;    -   A is a linear or branched, saturated or unsaturated hydrocarbon        divalent radical, with 1 to 18 carbon atoms, optionally being        substituted by 1 to 5 groups, either identical or different,        selected amongst —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR;        —NRR′; —NH—COR; Hal (halogen or even perhalogen); —CN; —COOR;        —COR; —NO₂; —SO₂OR;

-   with R and R′ representing, independently from each other, a linear,    branched or cyclic, saturated or unsaturated hydrocarbon radical,    with 1 to 6 carbon atoms, optionally being halogenated or even    perhalogenated;

-   said R and R′ radicals being able to form together with N a carbon    ring with 5 to 6 ring members optionally comprising further at least    one heteroatom selected amongst O, N and/or S in the ring and/or    optionally substituted by 1 to 5 groups, identical or different,    selected amongst —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂;    —NHR″; —NH—COR″; -Hal (halogen); —CN; —COOR″; —COR″; with R″    representing a linear, branched or cyclic, saturated or unsaturated    hydrocarbon radical having 1 to 6 carbon atoms, optionally being    halogenated, even perhalogenated;    -   B is a linear or branched, saturated or unsaturated hydrocarbon        radical having 1 to 18 carbon atoms, optionally substituted by 1        to 5 groups, either identical or different, selected amongst        —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR; —NRR′; —NH—COR;        Hal (halogen or even perhalogen); —CN; —COOR; —COR; —NO₂;        —SO₂OR;

-   with R and R′ representing, independently from each other, a linear,    branched or cyclic, saturated or unsaturated hydrocarbon radical    having 1 to 6 carbon atoms, optionally being halogenated or even    perhalogenated;

-   said R and R′ radicals being able to form together with N a carbon    ring with 5 to 6 ring members optionally comprising further at least    one heteroatom selected amongst O, N and/or S in the ring and/or    optionally substituted by 1 to 5 groups, identical or different,    selected amongst —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂;    —NHR″; —NH—COR″; -Hal (halogen); —CN; —COOR″; —COR″; with R″    representing a linear, branched or cyclic, saturated or unsaturated    hydrocarbon having 1 to 6 carbon atoms, optionally being halogenated    or even perhalogenated;    -   the X radical is a radical selected amongst —OH; —OR₄; —NH₂;        —NHR₄; —NR₄R₆; —SR₄; —COOR₄; —COR₄;

-   with R₄ and R₅ representing, independently from each other, a    linear, cyclic or branched, saturated or unsaturated hydrocarbon    radical having 1 to 6 carbon atoms, optionally substituted by 1 to 5    groups, identical or different, selected amongst —OH; —OR; —O—COR;    —SH; —SR; —S—COR; —NH₂; —NHR; —NH—COR; -Hal (halogen, even    perhalogen); —CN; —COOR; —COR; with R and R′ representing,    independently from each other, a linear, branched or cyclic,    saturated or unsaturated hydrocarbon radical having 1 to 6 carbon    atoms, optionally being halogenated or even perhalogenated; said R    and R′ radicals being able to form together with N a carbon ring    with 5 to 6 ring members optionally comprising further at least one    heteroatom selected amongst O, N and/or S in the ring and/or    optionally substituted by 1 to 5 groups, identical or different,    selected amongst —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂;    —NHR″; —NH—COR″; -Hal (halogen); —CN; —COOR″; —COR″; with R″    representing a linear, branched or cyclic, saturated or unsaturated    hydrocarbon radical having 1 to 6 carbon atoms, optionally being    halogenated or even perhalogenated; said R₄ and R₅ radicals being    able to form together with N a carbon ring with 5 to 6 ring members    optionally comprising further at least one heteroatom selected    amongst O, N and/or S in the ring and/or optionally substituted by 1    to 5 groups, identical or different, selected amongst —OH; —OR″;    —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″; —NH—COR″; -Hal (halogen);    —CN; —COOR″; —COR″; with R″ representing a linear, branched or    cyclic, saturated or unsaturated hydrocarbon radical having 1 to 6    carbon atoms, optionally being halogenated or even perhalogenated.

Are also included in such definition, the mineral or organic acid saltsof said compounds, as well as the optical isomers thereof, in anisolated form or as a racemic mixture.

It is meant by a linear, cyclic or branched hydrocarbon radical, amongstothers radicals of the alkyl, aryl, aralkyl, alkylaryl, alkenyl oralkynyl type.

The C₆H₅ group present in the R₃ radical should be understood as anaromatic cyclic group.

Preferably, the Y radical represents oxygen.

Preferably, the R₁ radical represents hydrogen or a linear or branched,saturated or unsaturated hydrocarbon radical having 1 to 12, moreparticularly 1, 2, 3, 4, 5 or 6 carbon atoms, optionally beingsubstituted. Amongst others, the substituants can be selected amongst—OH; —OR; and/or —P(O)—(OR)₂ with R representing a linear, branched orcyclic, saturated or unsaturated hydrocarbon radical having 1 to 6carbon atoms, optionally being halogenated, even perhalogenated.

More preferably, the R₁ radical represents a methyl, ethyl, propyl orisopropyl radical optionally substituted by a —OH or —P(O)—(OR)₂ groupwith R representing methyl, ethyl, propyl or isopropyl.

Preferably, the R₂ radical represents a linear, branched or cyclic,saturated or unsaturated hydrocarbon radical having 1 to 12, moreparticularly, 1, 2, 3, 4, 5 or 6 carbon atoms, optionally substituted.

Amongst others, the substituants can be selected amongst —OH and —ORwith R representing a linear, branched or cyclic, saturated orunsaturated hydrocarbon radical having 1 to 6 carbon atoms, optionallybeing halogenated, even perhalogenated.

More preferably, the R₂ radical represents a methyl, ethyl, propyl,isopropyl, n-butyl, ter-butyl or isobutyl radical.

Preferably, the R₃ radical represents a radical of the formula—C₆H_((5-y′))—B_(y′) where y′=1, 2 or 3; or a radical of the formula-A-C₆H_((5-y))—B_(y) where y=0, 1 or 2.

Preferably, A is a linear or branched, saturated or unsaturatedhydrocarbon divalent radical having 1 to 12 carbon atoms, optionallysubstituted.

The substituants for A are preferably selected amongst -Hal (halogen,even perhalogen); —CN; —COOR; —NO₂; —SO₂—OR; with R representing alinear, branched or cyclic, saturated or unsaturated hydrocarbon radicalhaving 1 to 6 carbon atoms, optionally being halogenated, evenperhalogenated.

Preferably, B is a linear or branched, saturated or unsaturatedhydrocarbon radical having 1 to 12 carbon atoms, optionally substituted.

The substituants for B are preferably selected amongst -Hal (halogen,even perhalogen); —CN; —COOR; —NO₂; —SO₂—OR; with R representing alinear, branched or cyclic, saturated or unsaturated hydrocarbon radicalhaving 1 to 6 carbon atoms, optionally being halogenated, evenperhalogenated.

More preferably, the R₃ radical is a group selected amongst one of thefollowing formulae:

where A and B have the meanings as hereabove.

More particularly, the divalent A radical can be a methylene, anethylene, a propylene.

The B radical is preferably a methyl, ethyl, propyl or isopropylradical, substituted by one or more halogens, more particularlychlorine, bromine, iodine or fluorine, and more preferably completelyhalogenated (perhalogenated) such as perfluorinated. The most preferredone is in particular the perfluoromethyl radical (—CF₃).

More preferably, the X radical represents a radical selected amongst —OHor —OR₄ with R₄ representing a linear, cyclic or branched, saturated orunsaturated hydrocarbon radical having 1 to 6 carbon atoms, optionallysubstituted.

The substituants can be selected amongst —OH and —OR with R representinga linear, branched or cyclic, saturated or unsaturated hydrocarbonradical having 1 to 6 carbon atoms, optionally being halogenated, evenperhalogenated.

More preferably, the X radical represents a radical selected amongst—OH, —OCH₃, —OC₂H₅, —O—C₃H₇ or —OC₄H₉.

The particularly preferred compounds include:

-   -   {2-[acetyl-(3-trifluoromethyl-phenyl)-amino]-3-méthyl-butyrylamino}acetic        acid,    -   {2-[acetyl-(3-trifluoromethyl-phenyl)-amino]-3-méthyl-butyrylamino}ethyl        acetate,    -   [2-(acetyl-benzyl-amino)-3-méthyl-butyrylamino]acetic acid,    -   [2-(acetyl-benzyl-amino)-3-méthyl-butyrylamino]ethyl acetate,        and    -   [2-{benzyl-[(diethoxy-phosphoryl)-acetyl]-amino}-3-méthyl-butyryl-amino]ethyl        acetate.

The compounds according to the invention can be easily prepared by theman of the art based on its general knowledge. It is more particularlypossible to react together a carboxylic acid, an aldehyde, an aminocompound and an isonitrile, according to Ugi reaction.

Obviously, upon the synthesis of the compounds according to theinvention and depending on the nature of the various radicals present onthe starting compounds, the man of the art will make sure to protectsome substituants so that they are not involved in the reactionsequence.

The compound quantity to be used in the compositions according to theinvention can be easily determined by the man of the art, depending onthe nature of the compound to be used, on the person to be treatedand/or the desired effect. Generally, this amount can range from 0.00001to 20% by weight based on the total weight of the composition,preferably 0.0001 to 5% by weight.

The compounds of the formula (I) can normally be used, in a compositioncomprising a physiologically acceptable medium, including in a cosmeticor pharmaceutical composition thus additionally comprising acosmetically or pharmaceutically acceptable medium.

The physiologically acceptable medium wherein the compounds according tothe invention can be used, as well as the components thereof, theiramount, the galenic form and its preparation mode, can be selected bythe man of the art based on its general knowledge depending on thedesired composition type.

Generally, such a medium can be anhydrous or aqueous. It can alsocomprise an aqueous phase and/a fatty phase.

Preferred Metalloproteinase Inhibitors

It is meant by “metalloproteinase inhibitor” according to the inventionany molecule and/or vegetable or bacterial extract showing an inhibitingactivity on the skin metalloproteinases.

Metalloproteinases are more particularly described in Y. HEROUY et al.,European Journal of Dermatology, n° 3, vol. 10, April-May 2000, pp.173-180.

The metalloproteinase family thus comprises several well defined groupsbased on their similarities in term of structure and substratespecificity (see Woessner J. F., Faseb Journal, vol. 5, 1991, 2145).Such groups can include collagenases adapted to degrade the fibrilcollagens (MMP-1 or interstitial collagenase, MMP8 or neutrophilcollagenase, MMP-13 or collagenase 3, MMP-18 or collagenase 4),gelatinases degrading the type IV collagen or any form of denaturedcollagen (MMP-2 or gelatinase A (72 kDa), MMP-9 or gelatinase B (92kDa)), stromelysins (MMP-3 or stromelysin 1, MMP-10 or stromelysin 2,MMP-11 or stromelysin 3), the broad activity spectrum of which addressesproteins of the extracellular matrix such as glycoproteins (fibronectin,laminin), proteoglycans, etc., matrilysin (MMP-7), metalloelastase(MMP-12) or even membrane metalloproteinases (MMP-14, MMP-15, MMP-16 andMMP-17).

The metalloproteinases (MMPs) are the members of a proteolytic enzymefamily (endoproteases) having a zinc atom coordinated with 3 cysteinresidues and with a methionine in their active site and degradingmacromolecular components of the extracellular matrix and basal lamellaeat a neutral pH (collagen, elastin, etc.). Very widely spread in theliving world, such enzymes are present, but weakly expressed, in normalphysiological situations such as organ growth and tissue renewal.

Their overexpression in man and their activation are however bound tonumerous processes involving the matrix destruction and restructuration.This leads, for example, to an uncontrolled resorption of theextracellular matrix.

Thus, a prolonged exposure to ultraviolet radiations, more particularlyto ultraviolet rays of the type A and/or B, has the effect ofstimulating the collagenase expression, particularly of the MMP-1. Thisis one of the components of the photoinduced skin ageing. Moreover, itis known that the activity of MMP-1, MMP-2 and MMP-9 increases over theage and that such an increase contributes, with the cell growth slowingdown, to the skin chronological ageing (WO 98/36742).

The metalloproteinases are produced and secreted under an inactive form(pro-enzyme). Such inactive forms, so-called zymogens, are thenactivated in the extracellular environment through elimination of apropeptid area. The members of this family can activate one another. TheMMP activity regulation occurs therefore at the level of the geneexpression (transcription and translation), at the level of the zymogenform activity, or at the level of the local control of the active forms.

The natural regulators of the MMP activity are the tissue inhibitors ofmetalloproteinases or TIMPs (tissue inhibitors of metalloproteinases).However, the expression of the MMPs is also modulated by the growthfactors, the cytokines, the oncogenic products (ras, jun) or even thematrix components.

It is meant by metalloproteinase inhibitor according to the invention,any molecule being able to regulate the MMP activity either at the levelof the gene expression (transcription and translation), either at thelevel of the activation of the MMP zymogen form activity, or also at thelevel of the local control of the active forms.

More preferably, a composition according to the invention ischaracterized in that the metalloproteinase inhibitor is selectedamongst an inhibitor of a metalloproteinase selected amongst MMP-1,MMP-2, MMP-3, MMP-7, MMP-9, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15,MMP-16 and MMP-17. The metalloproteinase inhibitor according to theinvention can be a natural inhibitor of metalloproteinases, particularlya tissue inhibitor of the metalloproteinases (TIMP) such as peptidesknown in the prior art under the names TIMP-1, TIMP-2, TIMP-3 and TIMP-4(Woessner J. F., Faseb Journal, 1991).

Alternatively, the metalloproteinase inhibitors suitable for use in thepresent invention may be MMP-1 inhibitors from natural or syntheticorigin. It is meant by “natural origin”, the metalloproteinase inhibitorin a pure state or in a solution at various concentrations, obtained bymeans of various exacting methods from an element, generally a plant,from natural origin. It is meant by “synthetic origin” themetalloproteinase inhibitor in a pure state or in a solution at variousconcentrations, obtained through chemical synthesis.

The metalloproteinase inhibitor can also be a natural extract containingursolic acid or carotenoids or vitamin C or isoflavones like thegenistein known for its metalloproteinase inhibiting activity (U.S. Pat.No. 6,130,254).

According to a preferred embodiment of the invention, ametalloproteinase inhibitor from natural origin is used, such aslycopene or an isoflavone. The lycopene activity on themetalloproteinases have been disclosed in Patent ApplicationEP-A-1090628.

According to another preferred embodiment, the metalloproteinaseinhibitor is a MMP-1 metalloproteinase transcriptional inhibitor, suchas retinol or the derivatives thereof, retinoic acid and the derivativesthereof. The inhibitors to be associated with can also be selectedamongst retinoic acid and the derivatives thereof, adapalene or alsoanalogous peptides and/or the derivatives of Batimastat ((BB94)=[4-(N-hydroxyamino)-2R-isobutyl-3S-(thiophen-2-ylthiomethyl)-succinyl]-L-phenylalanine-N-methylamide),of Marimastat ((BB2516)=[2S-[N4(R*),2R*,3S]]-N4[2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-N1,2-dihydroxy-3-(2-methyl-propyl)butanediamide)sold by the British Biotech corporation or also natural biologicalinhibitors such as the tissue inhibitors of metalloproteinases (TIMPs),as well as structural and/or functional analogs, even also inducers forsynthesis and/or release of such natural inhibitors. Sunscreens, byvirtue of an indirect action on metalloproteinase transcription et/orsynthesis, are also useful according to the invention.

More preferably, a composition according to the invention will containretinol as a metalloproteinase inhibitor.

Ideally, it will be possible to use such a novel association in carecosmetic preparations for sun exposed areas (scalp, body, face, lips)and, generally, in all the so-called “skin anti-ageing” cosmeticpreparations with the objective of slowing down the chronobiologicaldismantling of the backing tissues and the architecture of the skinmatrix elements.

The metalloproteinase inhibitor preferably represents 10⁻¹² to 5%, morepreferably 10⁻¹⁰ to 2% of the total weight of the composition.Obviously, if the metalloproteinase inhibitor is present in the form ofa solution containing a plant extract, the man of the art will be ableto adjust such a solution amount in the composition of the invention, soas to obtain the expected effect on the activity and/or the synthesisand/or the release of metalloproteinases.

The association of at least one N-acylaminoamide compound and at leastone metalloproteinase inhibitor can be used, more particularly, alone orin a mixture, in a composition comprising a physiologically acceptablemedium, in particular in a cosmetic or pharmaceutical composition which,therefore, comprises a cosmetically or pharmaceutically acceptablemedium.

The physiologically acceptable medium in which the compounds accordingto the invention can be used, as well as the components thereof, theiramount, the galenic form of the composition and its preparation mode,can be selected by the man of the art on the basis of its generalknowledge depending on the type of the desired composition.

Generally, such a medium can be anhydrous or aqueous. It can thuscomprise an aqueous phase and/or a fatty phase.

For applying onto the skin, the composition can have the form inparticular of an aqueous or an oily solution; of a dispersion of thelotion or serum type, of emulsions of liquid or semi-liquid consistencyof the milk type obtained through dispersion of a fatty phase into anaqueous phase (O/W) or reversely (W/O); of suspensions or emulsions of asoft consistency of the cream type or aqueous or anhydrous gel type; ofmicrocapsules or microparticles; of vesicular dispersions of the ionicand/or non ionic type.

For applying on the hair, the composition can be in the form of aqueous,alcoholic or hydroalcoholic solutions; in the form of creams, gels,emulsions, foams; in the form of aerosol compositions comprising apressurized propellant as well.

When the composition is in an aqueous form, in particular in an aqueousdispersion, emulsion or solution, it can comprise an aqueous phase,which may comprise water, flower water and/or mineral water.

Said aqueous phase can additionally comprise alcohols such as C₁-C₆monoalcohols and/or polyols such as glycerol, butyleneglycol, isopreneglycol, propyleneglycol, polyethyleneglycol.

When the composition according to the invention is in the form of anemulsion, it can optionally additionally comprise a surfactant,preferably in an amount ranging from 0.01 to 30% by weight based on thetotal weight of the composition. The composition according to theinvention can also comprise at least one co-emulsifier which can beselected amongst oxyethylenated sorbitan monostearate, fatty alcoholssuch as stearyl alcohol or cetyl alcohol, or esters of fatty acids andpolyols such as glyceryl stearate.

The composition according to the invention can also comprise a fattyphase, in particular made of fatty bodies liquid at 25° C., such as oilsfrom animal, vegetable, mineral or synthetic origin, either volatile ornot, fatty bodies solid at 25° C. such as waxes from animal, vegetable,mineral or synthetic origin; of pasty fatty bodies; of gums; and themixtures thereof.

The volatile oils are generally oils having, at 25° C., a saturatingvapor tension at least equal to 0.5 millibar (50 Pa).

Are included amongst the fatty phase components:

-   -   cyclic volatile silicones having 3 to 8 silicon atoms,        preferably 4 to 6,    -   cyclocopolymers of the dimethylsiloxane/methylalkylsiloxane        type,    -   linear volatile silicones with 2 to 9 silicon atoms,    -   hydrocarbon volatile oils, such as isoparaffins and, more        particularly, isododecane and fluorinated oils,    -   poly(C₁-C₂₀)alkylsiloxanes and, more particularly, those with        trimethylsilyl end groups, amongst which linear        polydimethylsiloxanes and alkylmethylpolysiloxanes such as        cetyldimethicone (CTFA name),    -   silicones modified by aliphatic and/or aromatic groups,        optionally fluorinated, or by functional groups such as        hydroxyl, thiol and/or amine groups,    -   phenylated silicone oils,    -   oils from animal, vegetable or mineral origin, in particular        animal or plants oils made of esters of fatty acids and polyols,        in particular liquid triglycerids, for example sunflower, corn,        soya, marrow, grape seed, sesame, hazelnut, apricot, almond, or        avocado oils; fish oils, glycerol tricaprocaprylate, or plant or        animal oils having the formula R₁COOR₂, where R₁ represents the        residue of a superior fatty acid having 7 to 19 carbon atoms and        R₂ represents a branched hydrocarbon chain having 3 to 20 carbon        atoms, for example Purcellin oil; paraffin oil, liquid paraffin,        perhydrosqualene, wheatgerm, calophyllum, sesame, macadamia,        grape seed, colza, copra, arachis, palm, castor, jojoba, olive        or cereal germ oils; fatty acid esters; alcohols;        acetylglycerides; octanoates, decanoates or ricinoleates from        alcohols or polyalcohols; fatty acid triglycerids; glycerids;    -   fluorinated and perfluorinated oils;    -   silicone gums;    -   waxes from animal, vegetable, mineral or synthetic origin, such        as microcrystalline waxes, paraffin, petrolatum, liquid        paraffin, ozokerite, Montan wax; beewax, lanolin, and the        derivatives thereof; Candelilla, Ouricury and Japan waxes,        cocobutter, cork fibre or sugar cane waxes; hydrogenated oils        solid at 25° C., ozokerites, fatty esters and glycerides solid        at 25° C.; polyethylene waxes and waxes obtained through        Fischer-Tropsch synthesis; hydrogenated oils solid at 25° C.;        lanolins; fatty esters solid at 25° C.; silicone waxes;        fluorinated waxes.

As it is known, the composition according to the invention can comprisethe usual builders in the field being involved, such as hydrophilic orlipophilic gelling agents, hydrophilic or lipophilic additives, actives,in particular hydrophilic or lipophilic cosmetic or pharmaceuticalactives, preservatives, antioxidants, solvents, perfumes, fillers,pigments, nacres, UV filters, odor absorbers and colorants. Suchbuilders, depending on their nature, can be introduced into the fattyphase, into the aqueous phase and/or into lipid spherules.

The nature and the amount of such builders can be selected by the man ofthe art, based on its general knowledge, so as to obtain the desiredpresentation form for the composition. Anyway, the man of the art willmake sure to select all the optional complementary compounds and/ortheir amount, so that the advantageous properties of the compositionaccording to the invention are not, or substantially not, altered by thecontemplated addition.

The cosmetic or pharmaceutical compositions according to the inventioncan, in particular, have the form of a composition designed for caringand/or treating ulcerated areas or which have been subjected to acutaneous stress or microstress, in particular generated by an exposureto the UV and/or the contact with an irritating product.

Accordingly, the compositions according to the invention can, inparticular, exhibit the form of:

-   -   a care, treatment, cleaning or protection product for the face        or the body skin, including the scalp, such as a (day, night,        hydrating) care composition for the face or the body; an        anti-wrinkle or anti-ageing composition for the face; a mating        composition for the face; a composition for the irritated skins;        a make-up removing composition; a body milk, in particular being        hydrating optionally an after-sun body milk;    -   a sun protective, artificial sun tanning (self-tanning) or        after-sun care composition;    -   a capillary composition, more particularly a sun protective        cream or gel; a scalp care composition, including an hair        restoring or hair growth composition; an anti-parasitic shampoo;    -   a face skin, body or lip makeup product, such as a foundation        cream, a tinted cream, a cheek or eye-lid makeup product, a free        or compact powder, an anti eye-ring stick, a concealing stick, a        lipstick, a lip care product; and    -   a mouth hygiene product, such as a tooth-paste or a mouthwash        lotion.

The compositions according to the invention find a preferred applicationas a composition for face skin care, of the anti-wrinkle or anti-ageingtype and as a sun protective or an after-sun composition.

The object of the present invention is also to provide a methodcomprising the steps of cosmetically treating the body or the face skin,in particular, the scalp, wherein a cosmetic composition is applied ontothe skin, comprising an association between a compound of theN-acylaminoamide family and at least a metalloproteinase inhibitor,leaving it in contact and optionally rinsing.

The cosmetic treatment method according to the invention can be appliedin particular by applying cosmetic compositions such as definedhereabove, according to the usual use technique of said compositions.For example: application of creams, gels, serums, lotions, make-upremoving milks or anti-sun compositions on the skin or on dry hair;application of a scalp lotion on wet hair, application of tooth-paste onthe gums.

The invention is illustrated in further detail in the followingexamples.

EXAMPLE 1

Preparation of{2-[acetyl-(3-trifluoromethyl-phenyl)-amino]-3-méthyl-butyrylamino}ethylacetate of the formula:

0.63 ml isobutyraldehyde and 1 ml trifluoromethylamine (1.15 eq) aremixed in 15 ml methanol under stirring. It is left to react for 15minutes at 20° C., thereafter 0.46 ml acetic acid are added (1.15 eq)and it is left to react for 10 minutes at 20° C. Then 0.8 ml 95% ethylisocyanoacetate (1 eq) are added and left to react for 48 hours at 20°C.

The reaction medium is concentrated using a rotovapor and the residue ispurified on a silica column (eluant: heptane: 3/ethyl acetate: 7;Rf=0.5).

2.45 g of a compound in the form of a waxy solid are obtained, whence a91% yield.

NMR¹H (200 MHz; CDC13) δ ppm: 0.9 (6H; q), 1.3 (3H; t), 1.8 (3H; s), 2.3(1H; m), 4.0 (2H, q), 4.2 (2H; q), 4.4 (2H; d), 7.3 (1H; t), 7.5 (4H;m).

EXAMPLE 2

Preparation of{2-[acetyl-(3-trifluoromethyl-phenyl)-amino]-3-méthyl-butyrylamino}aceticacid of the formula:

2 g of the compound prepared according to example 1 are solubilized in30 ml acetone. 30 ml 2N sodium hydroxyde are added and left to react for6 hours at 20° C. The reaction medium is concentrated using a rotovapor.The residual aqueous phase is acidified at pH 2 adding concentrated HCland then extracted with CH₂Cl₂.

The organic phase is dry concentrated after drying on sodium sulfate.

A residue is obtained which is solubilized with a base water mixture at10% ethanol and then again acidified with concentrated HCl at pH 2. Anew extraction by CH₂Cl₂ is performed, the organic phase is dried onsodium sulfate, filtered and dry concentrated under vacuum in arotovapor.

1.3 g of a compound are obtained in the form of a slight light brownsolid, whence a 70% yield.

NMR¹H (200 MHz; DMSO) δ ppm : 0.9 (6H; q), 3.7 (2H; m), 1.8 (4H; m), 4.8(2H; d), 7.6 (4H, q), 8.4 (1H; t), 12.5 (1H; s).

EXAMPLE 3

The anti-elastasic activity of compounds according to the invention isdetermined in vitro compared to the human leukocyte elastase (ELH).

The test is performed in the following way:

A Me-OSAAPV-p-NA (méthyl-O-succinate alanine alanine prolinevaline-p-nitroaniline) substrate, onto which ELH (40 milli-units per ml)and 0.1% of the compound to be tested are applied, is left forincubating at 37° C. for 60 minutes.

Thereafter, the % inhibition of the control elastase activity isdetermined by spectrophotometry,

The tested compounds are the following:

-   Compound A:    {2-[acetyl-(3-trifluoromethyl-phenyl)-amino]-3-méthyl-butyryl-amino}acetic    acid,-   Compound B:    (2-{benzyl-[(diéthoxy-phosphoryl)-acetyl]-amino}-3-méthyl-butyryl-amino)ethyl    acetate,-   Compound C: [2-(acetyl-benzyl-amino)-3-méthyl-butyrylamino]acetic    acid,-   Compound D: [2-(acetyl-benzyl-amino)-3-méthyl-butyrylamino]ethyl    acetate.

The following results are obtained:

Compound % Inhibition of the (concentration: 0.1%) control elastaseactivity Compound A 67% Compound B 17% Compound C 20% Compound D 13%

The same way, the % inhibition of the control elastase activity isdetermined for compound A, at various concentrations.

The following results are obtained:

Compound A % Inhibition of the concentration control elastase activity0.01% 53% 0.05% 50% 0.1%  68% 0.2%  68%

Compound A therefore generates a strong inhibition of the elastaseactivity, even in a small amount.

EXAMPLE 4

The ex vivo activity of example 2 compound has been evaluated onsurviving human skins treated by a human leukocyte elastase (ELH).

The test is performed the following way.

Fresh human skin cuts from two different donors are treated for 2 hours,at 20° C., by 20 μl of a buffer solution (pH 7.4) optionally comprising10 μg/ml ELH and optionally 0.1% of the compound to be tested,optionally previously put in solution in ethanol.

The elastic fibres are coloured in blue using catechin (+) andquantified morphometrically using a computer assisted image analysis.The average derma surface percentage occupied by elastic fibres isevaluated this way.

The following results are obtained:

% Surface occupied by elastic fibres Skin 1 Skin 2 Control (untreatedskin) 12.7% 15.25% ELH treated skin 4.85%  6.85% ELH treated skin +13.95% 11.85% example 2 compound

It is therefore found out that the compound according to the inventiongenerates a skin significant protection against the destruction ofelastic fibres induced by elastase.

EXAMPLE 5

The ex vivo activity of example 2 compound has been evaluated onsurviving human skins treated by a human leukocyte elastase (ELH).

The test is performed the following way:

Fragments of normal human skin from three different donors are depositedin inserts positioned in culture wells. Culture medium added withantibiotics is added in the bottom of the wells. A pass is performedthrough slow diffusion between the two compartments via a porousmembrane (pore size: 12 μm).

The culture medium is renewed every three days.

On the skin fragments, optionally 0.5 μg ELH per ml culture medium areadded.

5 μl of the compound to be tested are also added every two days,previously put in solution at 0.2% by weight in ethanol.

The skins are kept surviving for 10 days at 37° C.

The elastic fibres are coloured in blue using catechin (+) andquantified morphometrically using a computer assisted image analysis.The average derma surface percentage occupied by elastic fibres isevaluated this way.

The following results are obtained:

% Surface occupied by elastic fibres Control (untreated skin) 7.4% ELHtreated skin 5.1% ELK treated skin + example 2 7.1% compound

It is therefore found out that the compound according to the inventiongenerates a significant skin protection against the destruction ofelastic fibres induced by the elastase.

EXAMPLE 6

The activity of the example 2 compound has been evaluated on survivinghuman skins irradiated by UVA (8 J/cm²).

The test is performed the following way.

Fragments of normal human skin from four different donors are depositedin inserts positioned in culture wells. Culture medium added withantibiotics is added in the bottom of the wells. A pass is performedthrough slow diffusion between the two compartments via a porousmembrane (pore size: 12 μm).

The culture medium is renewed every three days.

On the skin fragments, every two days, 5 μl of a 0.2% solution of thecompound to be tested are added, in solution in ethanol.

The skins are kept surviving for 7 days at 37° C.

The skins are irradiated once at 8 J/cm² (RMX-3W Vilbert-Lourmat lamp).

The elastic fibres are coloured in blue using catechin (+) andquantified morphometrically using a computer assisted image analysis.The average derma surface percentage occupied by elastic fibres isevaluated this way.

The following results are obtained:

Elastic fibres Collagen morphometric morphometric analysis analysis(superficial (superficial derma) derma) Untreated skin 6.75% 87% UVAtreated skin 3.9% 81% (8 J/cm²) UVA treated skin 6.8% 92% (8 J/cm²) +compound

It is found out that the compound according to the invention does havean activity towards the destruction of elastic fibres in the UVAirradiated skin superficial derma.

This compound also exhibits an adequate effect on the collagenprotection.

EXAMPLE 7 Composition for Topic Application

The following emulsion is prepared conventionally (% by weight):

Compound from example 1  1% Retinol  0.1% Propylene glycol isostearate13% Polyethylene glyocl (8 OE)  5% Propylene glycol  3% Pentylene glycol 3% Glyceryl stearate and polyethylene glycol stearate (100 OE)  5%Oxyethylenated (20 OE) sorbitan monostearate  0.5% Oxypropylenated (20OE) oxyethylenated (5 OP) cetyl alcohol  1% Gelling agents  0.5% C₁₂-C₁₅alkyl benzoates  4% Ethanol  3% Sodium hydroxide  0.12% Preservatives qsWater qsp 100%

EXAMPLE 9 Face Care Cream

The following oil-in-water emulsion is prepared conventionally (% byweight):

Example 2 compound  1% Lycopene (in the form of Lycomato ® at 10% oflycopene  0.001% in a tomato oleoresin sold by Lycored ®) Glycalstearate  2% Polysorbate 60 (Tween 6O ® sold by ICI corporation)  1%Stearic acid  1.4% Triethanolamine  0.7% Carbomer  0.4% Shea butterliquid fraction 12% Perhydrosqualene 12% Antioxidant qs Perfume qsPreservative qs Water qsp 100%

EXAMPLE 9 Face Milk

The following milk is prepared according to the conventional way (% byweight):

Liquid paraffin 7% Genistein 0.2% Example 2 compound 1% Glycerylmonostearate, polyethylene glycol stearate (100 OE) 3% Carboxyvinylpolymer 0.4% Stearyl alcohol 0.7% Soya protein 3% NaOH 0.4% Preservativeqs Water qsp 100%

EXAMPLE 10 Hair Lotion

The following lotion is prepared conventionally (% by weight):

Example 1 compound  1% Retinol  0.01% Propylene glycol 23% Ethanol 55%Water qsp 100%

This lotion can be applied onto the scalp of alopecic people forpreventing the UV effects, before and/or after sun exposure.

EXAMPLE 11 Hair Restoring Lotion

The following lotion is prepared conventionally (% by weight):

Example 2 compound  1% Lycopene (in the form of Lycomato ® at 10% oflycopene  0.0001% in a tomato oleoresin sold by Lycored ®) Propyleneglycol 23% Ethanol 55% Aminexil  1.5% Water qsp 100%

This hair restoring lotion can be applied onto the scalp of alopecicpeople.

1. A composition comprising an N-acylaminoamide elastase inhibitor andat least one metalloproteinase inhibitor, wherein the elastase inhibitoris a compound of the formula (I):

where the Y radical represents O or S, the R₁ radical represents (i) ahydrogen atom, (ii) a linear, branched or cyclic, saturated orunsaturated hydrocarbon radical having 1 to 18 carbon atoms, optionallysubstituted by 1 to 5 groups, either identical or different, selectedfrom the group consisting of —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂;—NHR; —NRR′; —NH—COR; halogen; —CN; COOR; —COR; —P(O)—(OR)₂; —SO₂—OR;with R and R′ representing, independently from each other, a linear,branched or cyclic, saturated or unsaturated hydrocarbon radical having1 to 6 carbon atoms, optionally being halogenated; said R and R′radicals being able to form together with N a carbon ring with 5 to 6ring members optionally further comprising at least one heteroatom beingselected from the group consisting of O, N and S in the ring and/oroptionally substituted by 1 to 5 groups, identical or different,selected from the group consisting of —OH; —OR″; —O—COR″; —SH; —SR″;—S—COR″; —NH₂; —NHR″; —NH—COR″; halogen; —CN; —COOR″; and —COR″; with R″representing a linear, branched or cyclic, saturated or unsaturatedhydrocarbon radical, having 1 to 6 carbon atoms, optionally beinghalogenated; (iii) a radical selected from the group consisting of —OR;—NH₂; —NHR; —NRR′; —NH—COR; —COOR; —COR; with R and R′ representing,independently from each other, a linear, branched or cyclic, saturatedor unsaturated hydrocarbon radical having 1 to 6 carbon atoms,optionally being halogenated; said R and R′ radicals being able to formtogether with N a carbon ring with 5 to 6 ring members optionallycomprising, additionally, at least one heteroatom selected from thegroup consisting of O, N and S in the ring and/or optionally substitutedby 1 to 5 groups, identical or different, selected from the groupconsisting of —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″;—NH—COR″; halogen; —CN; —COOR″; and —COR″; with R″ representing alinear, branched or cyclic, saturated or unsaturated hydrocarbon radicalhaving 1 to 6 carbon atoms, optionally being halogenated; the R² radicalrepresents a linear, branched or cyclic, saturated or unsaturatedhydrocarbon radical, with 1 to 18 carbon atoms, optionally substitutedby 1 to 5 groups, either identical or different, selected from the groupconsisting of —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR; —NRR′;—NH—COR; halogen; —CN; —COOR; and —COR; with R and R′ representing,independently from each other, a hydrocarbon, linear, branched orcyclic, saturated or unsaturated radical, with 1 to 6 carbon atoms,optionally halogenated; said R and R′ radicals able to form togetherwith N a carbon cycle with 5 to 6 chains optionally comprising,additionally, at least one heteroatom selected from the group consistingof O, N and S in the ring and/or optionally substituted by 1 to 5groups, identical or different, selected from the group consisting of—OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″; —NH—COR″; halogen;—CN; —COOR″; and —COR″; with R″ representing a linear, branched orcyclic, saturated or unsaturated hydrocarbon radical, with 1 to 6 carbonatoms, optionally halogenated the R³ radical represents a radicalselected from formulae (II) or (III)-A-C₆H_((5-y))—B_(y)  (II)—C₆H_((5-y′))—B_(y′)  (III) where y is an integer between 0 and 5inclusive, and y′ is an integer between 1 and 5 inclusive; A is a linearor branched, saturated or unsaturated hydrocarbon divalent radical, with1 to 18 carbon atoms, optionally being substituted by 1 to 5 groups,either identical or different, selected from the group consisting of—OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂; —NHR; —NRR′; —NH—COR; halogen;—CN; —COOR; —COR; —NO₂; and —SO₂OR; with R and R′ representing,independently from each other, a linear, branched or cyclic, saturatedor unsaturated hydrocarbon radical, with 1 to 6 carbon atoms, optionallybeing halogenated; said R and R′ radicals being able to form togetherwith N a carbon ring with 5 to 6 ring members optionally comprisingfurther at least one heteroatom selected from the group consisting of O,N and S in the ring and/or optionally substituted by 1 to 5 groups,identical or different, selected from the group consisting of —OH; —OR″;—O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″; —NH—COR″; halogen; —CN;—COOR″; and —COR″; with R″ representing a linear, branched or cyclic,saturated or unsaturated hydrocarbon radical having 1 to 6 carbon atoms,optionally being halogenated; B is a linear or branched, saturated orunsaturated hydrocarbon radical having 1 to 18 carbon atoms, optionallysubstituted by 1 to 5 groups, either identical or different, selectedfrom the group consisting of —OH; —OR; —O—COR; —SH; —SR; —S—COR; —NH₂;—NHR; —NRR′; —NH—COR; halogen; —CN; —COOR; —COR; —NO₂; and —SO₂OR; withR and R′ representing, independently from each other, a linear, branchedor cyclic, saturated or unsaturated hydrocarbon radical having 1 to 6carbon atoms, optionally being halogenated; said R and R′ radicals beingable to form together with N a carbon ring with 5 to 6 ring membersoptionally comprising further at least one heteroatom selected from thegroup consisting of O, N and S in the ring and/or optionally substitutedby 1 to 5 groups, identical or different, selected from the groupconsisting of —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″;—NH—COR″; halogen; —CN; —COOR″; and —COR″; with R″ representing alinear, branched or cyclic, saturated or unsaturated hydrocarbon having1 to 6 carbon atoms, optionally being halogenated; the X radical is aradical selected from the group consisting of —OH; —OR₄; —NH₂; —NHR₄;—NR₄R₅; —SR₄; —COOR₄; and —COR₄; with R₄ and R₅ representing,independently from each other, a linear, cyclic or branched, saturatedor unsaturated hydrocarbon radical having 1 to 6 carbon atoms,optionally substituted by 1 to 5 groups, identical or different,selected from the group consisting of —OH; —OR; —O—COR; —SH; —SR;—S—COR; —NH₂; —NHR; —NH—COR; halogen; —CN; —COOR; —COR; with R and R′representing, independently from each other, a linear, branched orcyclic, saturated or unsaturated hydrocarbon radical having 1 to 6carbon atoms, optionally being halogenated; said R and R′ radicals beingable to form together with N a carbon ring with 5 to 6 ring membersoptionally comprising further at least one heteroatom selected from thegroup consisting of O, N and S in the ring and/or optionally substitutedby 1 to 5 groups, identical or different, selected from the groupconsisting of —OH; —OR″; —O—COR″; —SH; —SR″; —S—COR″; —NH₂; —NHR″;—NH—COR″; halogen; —CN; —COOR″; and —COR″; with R″ representing alinear, branched or cyclic, saturated or unsaturated hydrocarbon radicalhaving 1 to 6 carbon atoms, optionally being halogenated; said R₄ and R₅radicals being able to form together with N a carbon ring with 5 to 6ring members optionally comprising further at least one heteroatomselected from the group consisting of O, N and S in the ring and/oroptionally substituted by 1 to 5 groups, identical or different,selected from the group consisting of —OH; —OR″; —O—COR″; —SH; —SR″;—S—COR″; —NH2; —NHR″; —NH—COR″; halogen; —CN; —COOR″; and —COR″; with R″representing a linear, branched or cyclic, saturated or unsaturatedhydrocarbon radical having 1 to 6 carbon atoms, optionally beinghalogenated the mineral or organic acid salts thereof, the opticalisomers thereof, in an isolated form or as a racemic mixture.
 2. Acomposition according to claim 1, wherein the compound of formula (I) issuch that: the Y radical represents oxygen, and/or the R₁ radicalrepresents hydrogen or a linear or branched, saturated or unsaturatedhydrocarbon radical having 1 to 12 carbon atoms, optionally substituted,and/or the R₁ substituents being selected from the group consisting of—OH; —OR; and —P(O)—(OR)₂ with R representing a linear, branched orcyclic, saturated or unsaturated hydrocarbon radical having 1 to 6carbon atoms, optionally being halogenated; and/or the R₂ radicalrepresents a linear, branched or cyclic, saturated or unsaturatedhydrocarbon radical having 1 to 12, carbon atoms, optionallysubstituted, and/or the R₂ substituents being —OH or —OR with Rrepresenting a linear, branched or cyclic, saturated or unsaturatedhydrocarbon radical having 1 to 6 carbon atoms, optionally beinghalogenated; and/or the R₃ radical represents a radical of the formula—C₆H_((5-y′))—B_(y′) where y′=1, 2 or 3; or a radical of the formula-A-C₆H_((5-y))-By where y=0, 1 or 2; and/or the A radical of R₃ is alinear or branched, saturated or unsaturated hydrocarbon divalentradical having 1 to 12 carbon atoms, optionally substituted; and/or theB radical of R₃ is a linear or branched, saturated or unsaturatedhydrocarbon radical having 1 to 12 carbon atoms, optionally substituted;and/or A and/or for B are selected from the group consisting of halogen;—CN; —COOR, —NO₂; and —SO₂—OR; with R representing a linear, branched orcyclic, saturated or unsaturated hydrocarbon radical having 1 to 6carbon atoms, optionally being halogenated, and/or the X radicalrepresents —OH or —OR4 with R₄ representing a linear, cyclic orbranched, saturated or unsaturated hydrocarbon radical having 1 to 6carbon atoms, optionally substituted, and/or R₄ of X is —OH or —OR withR representing a linear, cyclic or branched, saturated or unsaturatedhydrocarbon radical having 1 to 6 carbon atoms, optionally beingsubstituted.
 3. A composition according to claim 1, wherein the compoundof the formula (I) is such that: the R₁ radical represents a methyl,ethyl, propyl or isopropyl radical, optionally substituted by a —OH or—P(O)—(OH)₂ group with R representing methyl, ethyl, propyl orisopropyl; and/or the R₂ radical represents a methyl, ethyl, propyl,isopropyl, n-butyl, ter-butyl or isobutyl radical; and/or the R₃ radicalrepresents a group of one of the following formulae:

where the divalent A radical is a methylene, ethylene, propylene and/orthe B radical is a methyl, ethyl, propyl or isopropyl radical,substituted by one or more halogens, and the X radical represents aradical selected from the group consisting of —OH, —OCH₃, —OC₂H₅,—O—C₃H₇ and —OC₄H9.
 4. A composition according to claim 1, wherein theelastase inhibitor is selected from the group consisting of:{2-[acetyl-(3-trifluoromethyl-phenyl)-amino]-3-methyl-butyrylamino}aceticacid,{2-[acetyl-(3-trifluoromethyl-phenyl)-amino]-3-methyl-butyrylamino}ethylacetate, [2-(acetyl-benzyl-amino)-3-methyl-butyrylamino]acetic acid,[2-(acetyl-benzyl-amino)-3-methyl-butyrylamino]ethyl acetate, and(2-{benzyl-[(diethoxy-phosphoryl)-acetyl]-amino}-3-methyl-butyryl-amino]ethylacetate.
 5. A composition according to claim 1, wherein the elastaseinhibitor is present in an amount ranging from 0.00001 to 20% by weightbased on the total weight of the composition.
 6. A composition accordingto claim 5, wherein the elastase inhibitor is present in an amountranging from 0.00001 to 5% by weight.
 7. A composition according toclaim 1, wherein the metalloproteinase inhibitor is an inhibitor of theactivity and/or the expression and/or the synthesis ofmetalloproteinases selected from the group consisting of MMP-1, MMP-2,MMP-3, MMP-7, MMP-9, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-16 andMMP-17.
 8. A composition according to claim 1, wherein themetalloproteinase inhibitor is a tissue inhibitor of metalloproteinases.9. A composition according to claim 1, wherein the metalloproteinaseinhibitor is a tissue inhibitor of at least one of TIMP-1, TIMP-2,TIMP-3 and TIMP4.
 10. A composition according to claim 1, wherein themetalloproteinase inhibitor is of natural origin.
 11. A compositionaccording to claim 1, wherein the metalloproteinase inhibitor representsfrom 10⁻¹² to 5% of the total weight of the composition.
 12. Acomposition according to claim 1, wherein the metalloproteinaseinhibitor represents from 10⁻¹⁰ to 2% of the total weight of thecomposition.
 13. A composition according to claim 1, comprising aneffective amount of said N-acylaminoamide elastase inhibitor and said atleast one metalloproteinase inhibitor to care for and/or treat ulceratedareas of the skin or areas of the skin having been subjected to acutaneous stress or microstress.
 14. A composition according to claim 1,in a form selected from the group consisting of: a care, treatment,cleaning or protection product, of the face, scalp or body skin; a sunprotective, artificial sun tanning (self-tanning) or after-sun carecomposition; a capillary composition; a face skin, body or lip make-upproduct; and a mouth hygiene product.
 15. A composition according toclaim 1, in the form of an anti-wrinkle, anti-ageing, sun protective orafter-sun composition for the face.
 16. A composition as claimed inclaim 1, wherein said composition is a cosmetic, dermatological, orcosmetic and dermatological composition.
 17. A composition according toclaim 1, wherein the metalloproteinase inhibitor is of synthetic origin.18. A composition according to claim 2, wherein the R₁ radicalrepresents hydrogen or a linear or branched, saturated or unsaturatedhydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, optionallysubstituted, and/or the R₂ radical represents a linear, branched orcyclic, saturated or unsaturated hydrocarbon radical having 1, 2, 3, 4,5 or 6 carbon atoms, optionally substituted.
 19. A compositioncomprising an N-acylaminoamide elastase inhibitor and at least onemetalloproteinase inhibitor, wherein the N-acylaminoamide elastaseinhibitor is a compound of the formula (I):

where the Y radical represents oxygen, the R₁ radical representshydrogen or a linear or branched, saturated or unsaturated hydrocarbonradical having 1 to 12, optionally substituted, the R1 substituentsbeing selected from the group consisting of —OH; —OR; and —P(O)—(OR)₂with R representing a linear, branched or cyclic, saturated orunsaturated hydrocarbon radical having 1 to 6 carbon atoms, optionallybeing halogenated; the R₂ radical represents a linear, branched orcyclic, saturated or unsaturated hydrocarbon radical having 1 to 12carbon atoms, optionally substituted, the R₂ substituents being —OH or—OR with R representing a linear, branched or cyclic, saturated orunsaturated hydrocarbon radical having 1 to 6 carbon atoms, optionallybeing halogenated; the R₃ radical represents a radical of the formula—C₆H_((5-y′))—B_(y′) where y′=1, 2 or 3; or a radical of the formula-A-C₆H_((5-y))-By where y=0, 1 or 2; the A radical of R₃ is a linear orbranched, saturated or unsaturated hydrocarbon divalent radical having 1to 12 carbon atoms, optionally substituted; the B radical of R₃ is alinear or branched, saturated or unsaturated hydrocarbon radical having1 to 12 carbon atoms, optionally substituted; A and/or for B areselected from the group consisting of -halogen; —CN; —COOR; —NO₂; and—SO₂—OR; with R representing a linear, branched or cyclic, saturated orunsaturated hydrocarbon radical having 1 to 6 carbon atoms, optionallybeing halogenated, and/or the X radical represents —OH or —OR4 with R₄representing a linear, cyclic or branched, saturated or unsaturatedhydrocarbon radical having 1 to 6 carbon atoms, optionally substituted,and R₄ of X is —OH or —OR with R representing a linear, cyclic orbranched, saturated or unsaturated hydrocarbon radical having 1 to 6carbon atoms, optionally being substituted.
 20. A composition comprisingan N-acylaminoamide elastase inhibitor and at least onemetalloproteinase inhibitor, wherein the N-acylaminoamide elastaseinhibitor is a compound of the formula (I):

where the R₁ radical represents a methyl, ethyl, propyl or isopropylradical, optionally substituted by a —OH or —P(O)—(OR)₂ group with Rrepresenting methyl, ethyl, propyl or isopropyl; the R₂ radicalrepresents a methyl, ethyl, propyl, isopropyl, n-butyl, ter-butyl orisobutyl radical; the R₃ radical represents a group of one of thefollowing formulae:

where the divalent A radical is a methylene, ethylene, propylene and/orthe B radical is a methyl, ethyl, propyl or isopropyl radical,substituted by one or more halogens, and the X radical represents aradical selected from the group consisting of —OH, —OCH₃, —OC₂H₅,—O—C₃H₇ and —OC₄H₉.